Targeting the release of anorectic and antidiabetic gut peptides is the focus of many ongoing drug development programs, as evidence is accumulating that enhanced secretion of Peptide YY (PYY) and Glucagon-Like Peptide-1 (GLP-1) from intestinal L-cells may translate into beneficial effects in subjects with diabetes and obesity.
Short chain fatty acids (SCFA), derived from bacterial fermentation of macrofibrous material reaching the distal gut are known to reach high concentrations under physiological conditions in the colons of healthy subjects. Non-digestible and fermentable dietary fibre, as well as SCFA themselves, have been shown to increase GLP-1 and PYY secretion in humans (Zhou et al., Am. J. Physiol. Endocrinol. Metab., 2008, vol. 295(5), pp. E1160-E1166), and enhanced PYY release has been proposed as a link between luminal SCFA and altered gut motility (Dumoulin et al., Endocrinology, 1998, vol. 139(9), PP. 3780-3786).
SCFA act as a local nutrient source, but can also trigger cell-specific signalling cascades by activation of the G-protein coupled free fatty acid receptors, GPR41 (FFAR3) and GPR43 (FFAR2) (Brown et al., J. Biol. Chem., 2003, vol. 278(13), pp. 11312-11319). The finding that both receptors are located in colonic L cells by immunostaining (Tazoe et al., Biomed. Res., 2009, vol. 30(3), PP. 149-156), suggests that short chain fatty acids may utilise this pathway to modulate L-cell function. In addition to L cells, GPR43 is also expressed in Islets of Langerhans, white adipose tissue, bone marrow and spleen.
GPR43 knockout mice have impaired glucose tolerance, with reduced insulin secretion and reduced GLP-1 secretion (Tolhurst et al., Diabetes, 2012, vol. 61, pp. 364-371). They have increased fat mass and a mild increase in food intake. From this it can be deduced that activation of the GPR43 receptor should lead to beneficial effects in the treatment of diabetes and obesity.
GPR43 is also expressed on a variety of immune cells, so may represent a potential treatment for certain inflammatory diseases and conditions (Bindels L B, Dewulf E M, Delzenne N M., Trends Pharmacol Sci., 2013, 34(4), PP. 226-32; Macia L et al., Nat Commun, 2015, 6, article 6734; and Smith, P M et al., Science, 2013, 341 (6145), PP. 569-573).
There is therefore a need for compounds that activate the GPR43 receptor.
Certain 3-substituted 2-amino-indole analogues are known in the art. WO 2004/060893 describes a broad class of such compounds useful for treating a variety of diseases modulated by potassium channels. Other substituted indole analogues are known from WO 2012/064897, WO 2005/023818, WO 2011/140164, WO 2011/153553 and US 2014/0018361.